Exposure to cosmetic talc and mesothelioma

Aim Mesothelioma is associated with asbestos exposure. In this case series, we present 166 cases of individuals who had substantial asbestos exposure to cosmetic talc products as well as some who had potential or documented additional exposures to other asbestos-containing products and who subsequently developed mesothelioma. Methods Data were gathered for all subjects referred to an occupational and environmental medicine specialist as part of medicolegal review. Years of total cosmetic talcum powder usage was noted as well as the latency from the onset of talcum powder use to the mesothelioma diagnosis. Alternate asbestos exposure in addition to the exposure from cosmetic talc was categorized as none, possible, likely, and definite. Results In 122 cases, the only known exposure to asbestos was from cosmetic talc. For 44 cases, potential or documented alternate exposures in addition to the cosmetic talc were described. Conclusion Cumulative exposure to asbestos leads to mesothelioma; for individuals with mixed exposures to asbestos, all exposures should be considered. Use of cosmetic talc is often overlooked as a source of asbestos exposure. All individuals with mesothelioma should have a comprehensive history of asbestos exposure, including cosmetic talc exposure.


Introduction
Mesothelioma, described as a sentinel tumor, is intimately associated with asbestos exposure. Asbestos has been used for decades in thousands of products, both in occupational and non-occupational settings, historically accounting for the bulk of mesothelioma cases. Nonoccupational exposures can be environmental in nature, from effluents from mines and factories, from paraoccupational exposures such as "shade-tree mechanics" using friction products, and from home renovations [1]. Household exposures affecting family members, known as "take-home" exposure has been well described in the literature [2][3][4][5]. An underappreciated source of exposure is the use of cosmetic talc products. The International Agency for Research on Cancer (IARC) [6] states that asbestos contaminated talc is carcinogenic and should be treated as if one were dealing with asbestos. Asbestos levels in talcum powder are significantly above background ambient asbestos exposure levels [7][8][9]. Talc application simulation studies have been published [7,8] where exposures to talcum powder were 1.9 f/cc and 2.57 f/cc, respectively. According to the Gramond et al. [10] categorization of intensity, asbestos exposure at these levels would be considered to be high (> 1-10 f/ml).
Historically, asbestos exposures at work have been linked to multiple products. The overall risk for asbestos related disease, including mesothelioma, is related to cumulative exposure. As agencies such as NIOSH, OSHA, the EPA, and others have recognized, there is no known safe exposure to asbestos. Low doses of exposure to asbestos contribute to mesothelioma [11].
Both time from first exposure (latency) and total exposure (cumulative dose) to asbestos must be taken into account when evaluating risk. With multiple repeated incidences of exposure, all those above background level should be thought of as "'substantial. " When considering the elevated risk of mesothelioma in sheet metal workers [12,13], Zoloth and Michaels considered the multiple bystander exposures to different products, not simply one construction material. This case series presents 166 cases of individuals who had a minimum of five years and a mean of 40.8 years of exposure to asbestos through cosmetic talc products, some with possible other exposures, but all developed mesothelioma.

Methods
Data were gathered for all subjects referred to an occupational and environmental medicine specialist, JM, as part of medicolegal review. All cases were reviewed personally by an occupational medicine specialist with experience evaluating asbestos exposure in thousands of individuals. The individual's medical records were reviewed and mesothelioma diagnoses were based on pathological reports that were performed as part of their diagnostic evaluation. Exposure data was obtained by sworn testimony of the mesothelioma patients in all cases, and/or from family members who had direct knowledge of the individual's use of cosmetic talc and, if present, other sources of asbestos exposure. Use of talc was recorded as being diapered or powdered as a child; diapering or powdering children or others; applying talcum powder to oneself after bathing, or other personal applications of talc. Years of total cosmetic talcum powder usage was noted as well as the latency from the onset of talcum powder use to the mesothelioma diagnosis. Age was presented within a 10 year window to maintain confidentiality. Data reviewed included family occupational histories (parents or anyone cohabitating with the individual), hobbies, residence, living with or laundering clothes of an asbestos exposed worker, if indicated, home renovations that could have exposed the individual to asbestos containing construction materials, residence close to a facility with environmental contamination, or other potential asbestos exposures. In those individuals with potential asbestos exposure in addition to the cosmetic talc, categorization of these exposures was done by two occupational physicians, JM and ALF. Alternate asbestos exposure in addition to the exposure from cosmetic talc was categorized as none, possible, likely, and definite following the descriptions by Gramond et al. [10]. Nonoccupational exposure to asbestos was characterized as paraoccupational (living with an asbestos worker or cleaning clothes), do-it-yourself home repair, domestic (handling asbestos material or living in the presence of asbestos material susceptible to damage at home), or environmental (living near and asbestos processing plant). This study was conducted with approval from the Human Research Protection Program at Northwell Health Feinstein Institute for Medical Research (#21-0897-OTH).

Results
We identified 166 individuals with exposure to cosmetic talc who were diagnosed with a malignant mesothelioma between 2014 and 2021. None of these individuals were previously included in publications by the authors [14]. A summary of the case findings is found in Table 1. Overall, the average age of diagnosis was 63.3 (age range 26-94) years of age. The majority of cases were epithelioid mesothelioma (75.3%). The average length of exposure to cosmetic talc was 40.8 years (range 5-76 years of use), and the average latency period from the onset of talcum powder use to the development of mesothelioma was 52.4 (20-83 years). We identified 122 individuals with asbestos exposure solely through use of cosmetic talc. Exposure to talcum powder could have been for personal use, in an occupational setting (for example, a nurse applying talcum powder to a patient), or applying talcum powder to others such as children. For 122 individuals, they either used cosmetic talc while diapering children or recalled applying talc to others (such as their children). Overall, 80.6% of women and 52.4% of men used talcum powder for diapering or applying talc to others. For 44 individuals, potential alternate asbestos exposure in addition to cosmetic talc was reported. Table 1 presents the 44 cases with alternate exposure ranked by possible, likely, and definite asbestos exposure. Twenty-two women (17.8%) and fifteen men (35.7%) had likely or definite alternate exposure to asbestos in addition to their talcum powder usage. [Details of the exposure history of all 166 individuals with cosmetic talc exposure is presented in Table 2, including a description of the alternate exposure.] Table 1 also shows the site of the tumor by gender. Of the 166 cases, 109 were pleural, 52 were peritoneal, 4 were discovered in both the pleura and peritoneum and the original site could not be determined. One case of pericardial mesothelioma was noted out of the 166 cases, which reflects the rarity of this site for mesothelioma. The percentages of peritoneal mesothelioma were similar for women (29.8%) and men (35.7%). The high proportion of peritoneal mesothelioma tumors relative to pleural tumors, consistent with prior case series of patients with malignant mesothelioma after cosmetic talc use [14,15], is unusual and deserves further investigation.

Discussion
This paper presents 166 individuals with malignant mesothelioma and asbestos exposure through documented use of cosmetic talcum powder. For 122 of 166, their only known exposure to asbestos was their use of cosmetic talcum powder. Without the recognition of asbestos exposure through cosmetic talcum powder, 73.5% of the cases might well have been considered "idiopathic. " Similarly, for those 26.5% of cases with additional asbestos exposure along with the talc, those alternate exposures would have been mistakenly considered as the sole, and sufficient, cause of the mesothelioma. Historically, the attributable risk of asbestos for mesothelioma in women ranged from around 20-50%. However as Baur et al. point out, misclassification or inadequate exposure ascertainment has led to this low attributable risk for women compared to men. [16]. Data from occupationally exposed cohorts that included men and women actually show that compared to similarly exposed men, women had higher mortality rates from mesothelioma [17][18][19][20]. Lacourt found that at low-level cumulative asbestos exposure ((0 -0.1 f-cc/ year) women were more likely to develop mesothelioma than men [21]. Magnani (2008) found the SMR for mesothelioma was higher for women than for men among workers at an asbestos cement plant [22]. Frank et al. (2009) found mesothelioma rates in the Qingdao region of China were correlated with a higher proportion of women employed in asbestos manufacturing industries. [23] In some instances authors limited the characterization of asbestos exposure in women to certain industries, such as shipbuilding during wartime [24], thus neglecting other potential sources and decreasing the attributable risk. Conversely, when non-occupational exposures were included for women, even with low-intensity domestic exposure considered, the attributable risk increased from 40% to 64.8% [21]. Given that all types of asbestos can cause mesothelioma [6], it is important to consider every source of exposure to asbestos in an individual. Talcum powder has been contaminated with both chrysotile and amphibole asbestos (predominately anthophyllite and tremolite) [8,25,26]. Recently, Wong et al. (2021) found significantly elevated risks of mesothelioma among individuals with only chrysotile exposure and for mixed fiber exposure. [27]. Chrysotile alone (OR = 3.8) and in combination with tremolite/anthophyllite asbestos (OR = 3.9) were associated with similar increases in risk of mesothelioma. These three fiber types are most commonly found in cosmetic talc, and given that different ore sources were used in manufacturing over time, it is likely that many formulations and uses of talcum powder involved mixed fiber type exposure. There is no scientific basis to state that one type of exposure was the sole cause of the mesothelioma in a mixed exposure scenario. For example, rates of mesothelioma have been evaluated based on either job type or locale (e.g., construction, shipping) rather than Table 1 Characteristics of 166 mesothelioma cases with cosmetic talc usage * Years of Talc Use: includes years of being diapered or powdered with talc as a child; years of diapering or powdering children or others with talc; and years applying talcum powder to oneself after bathing or other personal use ** Diapering or Applying Talc: restricted to diapering or powdering children with talc or applying talcum powder to others, including occupational use       on each specific task or exposure within the job category. Furthermore, mesothelioma is a disease that occurs following a long latency period. It is important to consider whether the latency period for all exposures, whether due to asbestos in talcum powder, or through occupational or para-occupational exposures meets the minimum latency period. Subgroups of individuals not traditionally known to be exposed to asbestos have been identified, such as teachers. In this case series, 12 teachers (7.2% of cases) were diagnosed with mesothelioma. Anderson et al. identified 12 school teachers with mesothelioma in Wisconsin (6 male, 6 female). [28]. Nine cases had no known exposure to asbestos, although several worked in school buildings with asbestos containing building materials (ACBM) present, but the condition of the ACBR while the teachers were present in the school was unknown. No history of talcum powder use was elicited. Marianaccio et al. identified mesotheliomas in 11 female teachers in Italy. [29].
Mazurek et al. evaluated mesothelioma deaths in women in the United States from 1999-2020 using death certificate data. [30]. Mesothelioma was noted in 32 female elementary and middle school teachers. No information on exposure to asbestos or specific tasks at work or a comprehensive exposure history was available; no history of talcum powder use was elicited, as the study was based solely on death certificates. Tomasallo et al. found increased mortality among school teachers in Wisconsin, USA. [31]. They noted that para-occupational or take home exposure could be responsible for the increased risk. Again, no history of asbestos exposure through talcum powder usage was ascertained. It might be possible that exposure to ACBM played some role in these mesotheliomas, however, the notable history of exposure to asbestos-containing talcum powders among teachers in this case series, highlights the importance of assessing this source of exposure in future studies of mesothelioma in teachers and other predominantly female professions.
Mazurek et al. found seven cases of mesothelioma among female hairdressers. [30]. Our series identified five hairdressers/barbers with documented occupational exposure to asbestos containing talcum powder. Moline et al. found three hairdressers who used cosmetic talc as part of their occupation, [14] and Emory et al. [15] found 4 hairdressers out of 75 patients. Pavlisko et al. identified a hairdresser in their study of mesothelioma in women, but classified the case in the non-occupational/paraoccupational exposure category. [32] McDonald attributed the finding of tremolite in the lung tissue of a chrysotile worker to his prior occupational exposure to talc as a barber [33]. Rodelsberger recognized talc as a source of asbestos exposure and identified hairdressers and barbers as asbestos-exposed industries [34]. The examples of these two occupational subgroups, teachers with personal use of cosmetic talc, and hairdressers with occupational use of cosmetic talc, show the importance of obtaining a thorough history and determining all potential sources of asbestos exposure.
This case series describes mesotheliomas in end-users of cosmetic talcum powder, thus using no personal protective equipment or dust suppression activities, unlike some cohorts with occupational exposures [35]. Prior mortality studies of talc miners and millers in Italy (and other countries) have not identified mesotheliomas in their populations, although two cases of peritoneal cancer were identified by Pira et al. [36]. The Rubino, Coggiola and Pira et al. studies used mortality data collected prior to an ICD mesothelioma code, which could impact proper classification of mesothelioma. [35][36][37]. The studies had a relatively small sample size, which given the rarity of mesothelioma, even among highly exposed individuals, would have led to insufficient statistical power [38]. Fordyce studied Vermont talc miners and found two mesotheliomas in the small cohort of 427 miners; Vermont talc has been used in cosmetic talcum powder [39].
Fiber burden studies were done in some individuals from the two prior case series of mesothelioma among individuals with cosmetic talcum powder use. Moline et al. reported on tissue fiber analysis in six of 33 individuals. Asbestos fibers, of the types found in cosmetic talc, were found in all six samples. Emory et al. found anthophyllite asbestos in all 9 individuals for whom tissue fiber analysis was done. Tremolite was found in six of the cases in addition to the anthophyllite. Hull et al. [40] looked at New York State talc miners and found anthophyllite, tremolite/actinolite, chrysotile and talc in their lungs. There were over a dozen cases of mesothelioma identified in these talc miners. Our case series did not include data on tissue sampling, which is not typically done for clinical purposes; rather we relied on patient history. For occupational exposures to asbestos, fiber analysis is not required to ascertain a history of exposure, rather the history of exposure to asbestos is sufficient [41]. This should be no different for environmental exposures, such as asbestos exposure in cosmetic talcum powder, or even para-occupational exposures.
Pleural mesothelioma is more common than peritoneal mesothelioma [42], with estimates of pleural mesothelioma occurring approximately 80-90% of the time compared to peritoneal mesothelioma. The presenting location for the tumor, either pleural or peritoneal, was similar in all three recent case series. In Moline et al., 11 of 33 patients had peritoneal mesothelioma and in Emory et al., 23 of 75 cases were peritoneal mesothelioma. In this larger case series, the proportion of peritoneal mesotheliomas was 31.3%. The proportion of men  20.5% were men, slightly above the proportion in two previous case series. This might reflect growing awareness among men that talcum powder use could explain their mesothelioma, particularly when no other identifiable source of asbestos was identified. Few individuals in this case series underwent testing for the tumor suppressor gene, BAP-1, which is associated with an increased risk for mesothelioma when associated with asbestos exposure, [43] including greater susceptibility at low doses of asbestos such as exposures from cosmetic talcum powder use. Interestingly, there was a greater frequency of peritoneal mesothelioma cases in those with the BAP-1 mutation and asbestos exposure [44].
Several authors have written about the importance of the cumulative dose, which has been related to several asbestos-caused diseases, both non-malignant and non-malignant. Luberto et al. discussed the "increased mortality risk due to asbestos exposure for malignant neoplasm of pleura, peritoneum, lung and ovary, as well as asbestosis, all increasing with cumulative exposure. " [19] Henderson et al. commented on the use of the cumulative exposure model in the Helsinki Criteria. [45] Iwastsubo and colleagues, citing only low exposures leading to disease noted that "excess of mesothelioma was observed for levels of cumulative exposure. " [46] Ferrante and her colleagues [47] found that the "risk of pleural malignant mesothelioma increased with cumulative asbestos exposure and also in analyses limited to subjects non-occupationally exposed, " comparable to the current case series. Albin et al. [48] even noted that "colorectal cancer displayed a clear relation with cumulative dose, " as one would reasonably expect with asbestos-related diseases.
This case series may reflect the potential sources of bias that impact all studies that use cases in which litigation is occurring. However, because mesothelioma is a rare disease and full environmental histories are rarely obtained or documented, it would be impossible to amass so many cases with one type of exposure using standard sources such as hospital or cancer registry records. Furthermore, most patients (and their clinicians) are unaware of the presence of asbestos in talcum powder, leading them to report no known asbestos exposure. The data related to years of exposure to cosmetic talcum powder was obtained and typically described in great detail during sworn testimony. For nearly one-quarter of the individuals in this series, additional exposures to asbestos were reported along with the cosmetic talcum powder. When available, information regarding talcum powder usage was corroborated by sworn testimony of family members. Typically, the questioning of individuals about alternate exposures to asbestos as part of litigation is fairly comprehensive, but it is possible that there were additional, unknown sources. This presents a challenge for any study of asbestos exposure and, in particular, mesothelioma, given the long latency period from the onset of exposure to the development of disease.

Conclusion
For individuals with exposure to asbestos through cosmetic talc usage and additional alternate sources, all exposures contribute to the development of mesothelioma. Published case reports and case series have identified over 100 individuals whose sole exposure to asbestos was through cosmetic talcum powder usage [14,15,49]. Thus, is it critical to obtain a history of all potential exposures to asbestos. In this case series, 122 cases would have had no source of asbestos identified if a history of asbestos-containing cosmetic talc had not been elicited. The other 44 would have likely been misclassified as having only alternate exposures. It is indisputable that asbestos causes mesothelioma, therefore, it is critical to elicit all potential sources of asbestos exposure so that we can better understand, and prevent, future cases of this deadly cancer.